Effects of cathelicidin on coagulation and venous thromboembolism

Zhang, Qing (2023): Effects of cathelicidin on coagulation and venous thromboembolism. Dissertation, LMU München: Faculty of Medicine

Abstract

Venous thromboembolism is a common vascular disease with high mortality and morbidity. Virchow triad (reduced blood flow velocity, hypercoagulability and endothelial activation) are still considered main pathophysiological factors in the development of venous thrombosis. Over the recent years inflammation has established as another key mechanism that triggers and propagates venous thromboembolism. Leukocyte-released cathelicidin are antimicrobial peptides that play a critical role in mammalian innate immune defense and modulation of inflammation. Our group recently showed that cathelicidin induce platelet activation with consecutive formation of neutrophil extracellular traps (NETs) and that absence of cathelicidin reduces thrombo-inflammation including arterial thrombosis. However, effects of cathelicidin on the coagulation system have been controversially discussed and their role in venous thrombosis, where neutrophils and NETosis are key features, so far has not been investigated. This work shows that human cathelicidin LL-37 is abundant in thrombi from patients with deep vein thrombosis. Its mouse homologue, CRAMP, is systemically increased in plasma in mice that developed venous thrombosis after flow reduction by vena cava ligation and is found locally within thrombi. Cathelicidin mainly presents in close proximity of neutrophils and in vitro neutrophil activation triggers both, release of the soluble peptide as well its presentation on extracellular DNA (NETs). In human platelet-rich-plasma LL-37 moderately accelerates clot formation and thickness induced by activation of the extrinsic (but not intrinsic) coagulation pathway in a platelet-dependent manner. Proteome analysis of cathelicidin-stimulated washed platelets reveals upregulation of platelet-derived factor VII-activating protease (FSAP) and vitronectin (VTN) as possible mechanistic explanations for our observations. In vivo, absence of hematopoietic CRAMP in flow reduction-triggered venous thrombosis does not affect incidence and local thrombus size but reduces local macrophage infiltration in the thrombus adjacent vascular wall and pulmonary embolization/platelet burden. In conclusion, cathelicidin-induced platelet activation propagates extrinsic blood coagulation in vitro. While neutrophil-derived cathelicidin is dispensable for incidence and size of venous thrombosis in vivo, we provide evidence that it fosters local vascular inflammation and thrombo-embolization to the lung.

• Item Type: Theses (Dissertation, LMU Munich)
• Keywords: cathelicidin, neutrophil, immunothrombosis, platelet, venous thrombosis
• Subjects: 600 Technology, Medicine; 600 Technology, Medicine > 610 Medical sciences and medicine
• Faculties: Faculty of Medicine
• Language: English
• Date of oral examination: 24. May 2023
• 1. Referee: Schulz, Christian
• Signature of the printed copy: 0700/UMD 22795